Expanded Newborn Screening for Inborn Errors of Metabolism in Hong Kong: Results and Outcome of a 7 Year Journey.

Newborn screening (NBS) is an important public health program that aims to identify pre-symptomatic healthy babies that will develop significant disease if left undiagnosed and untreated. The number of conditions being screened globally is expanding rapidly in parallel with advances in technology, diagnosis, and treatment availability for these conditions. In Hong Kong, NBS for inborn errors of metabolism (NBSIEM) began as a pilot program in October 2015 and was implemented to all birthing hospitals within the public healthcare system in phases, with completion in October 2020. The number of conditions screened for increased from 21 to 24 in April 2016 and then to 26 in October 2019. The overall recruitment rate of the NBS program was 99.5%. In the period between October 2015 and December 2022, 125,688 newborns were screened and 295 were referred back for abnormal results. The recall rate was reduced from 0.26% to 0.12% after the implementation of second-tier testing. An inherited metabolic disorder (IMD) was eventually confirmed in 47 infants, making the prevalence of IMD in Hong Kong 1 in 2674. At the time of the NBS result, 78.7% of the newborns with IMD were asymptomatic. There were two deaths reported: one newborn with methylmalonic acidemia cobalamin B type (MMACblB) died after the initial crisis and another case of carnitine palmitoyltransferase II deficiency (CPTII) died at 18 months of age after metabolic decompensation. The most common IMD noted were disorders of fatty acid oxidation metabolism (40%, 19 cases), closely followed by disorders of amino acid metabolism (38%, 18 cases), with carnitine uptake defect (19.1%, 9 cases) and citrullinemia type II (17%, 8 cases) being the two most common IMD picked up by the NBSIEM in Hong Kong. Out of the all the IMDs identified, 19.1% belonged to diverse ethnic groups. False negative cases were reported for citrullinemia type II and congenital adrenal hyperplasia during this period.

Review on the screening of urine glucose for early diagnosis of type 2 diabetes mellitus in school children and adolescents with obesity in Hong Kong.

OBJECTIVES: Obesity and type 2 diabetes mellitus (T2DM) are growing health concerns. Since 2005, Student Health Service (SHS) and Hong Kong Paediatric Society formulated a protocol on urine glucose screening (UGS) for early diagnosis of T2DM in students with obesity in Hong Kong. This study reviews students with T2DM captured by this screening program and compare the data with the Hong Kong Children Diabetes Registry (HKCDR) database, to see if the UGS program facilitates early diagnosis of T2DM. METHODS: Students between the ages of 10-18 years old with age- and sex-specific body mass index (BMI) >97th percentile who attended SHS between the school years from 2005/06 to 2017/18 were recruited for UGS. Those tested positive for random urine glucose underwent diagnostic testing for T2DM according to ADA guidelines. Demographic data and investigatory results from UGS and HKCDR within the same time period were compared. RESULTS: A total of 216,526 students completed UGS in the said period; 415 (0.19 %) students were tested positive for urine glucose of which 121 students were diagnosed with T2DM. UGS picked up 23 % of the newly diagnosed T2DM cases. When compared to the HKCDR database, students diagnosed via UGS were significantly younger, less obese, and had fewer diabetic related complications. The negative predictive value of UGS is high and can effectively rule out T2DM. CONCLUSIONS: Urine glucose screening is an inexpensive and simple test that allows for early diagnosis of T2DM among obese school students. Other methods including POCT HbA1c can be explored to improve program effectiveness.

Diabetic ketoacidosis in children with new-onset type 1 diabetes mellitus: demographics, risk factors and outcome: an 11 year review in Hong Kong.

OBJECTIVES: Diabetic ketoacidosis (DKA) is a life-threatening complication of type 1 diabetes (T1D). The aim of this study is to analyze the incidence, clinical characteristics, management and outcome of children presenting with DKA in new-onset T1D from 2008 to 2018 in Hong Kong. METHODS: Data was extracted from the Hong Kong Childhood Diabetes Registry. All subjects less than 18 years with newly diagnosed T1D from 1 January 2008 to 31 December 2018 managed in the public hospitals were included. Information on demographics, laboratory parameters, DKA-related complications and management were analyzed. RESULTS: In the study period, there were 556 children with newly diagnosed T1D in our registry and 43.3% presented with DKA. The crude incidence rate of new-onset T1D with DKA was 1.79 per 100,000 persons/year (CI: 1.56-2.04). Subjects presenting with DKA were younger (9.5 ± 4.5 vs. 10.5 ± 4.4, p=0.01) and had shorter duration of symptoms (4.2 ± 5.9 days vs. 10.6 ± 17.1 days, p<0.01). Regarding management, up to 12.4% were given insulin boluses and 82.6% were started on insulin infusion 1 h after fluid resuscitation. The rate of cerebral edema was 0.8% and there was no mortality. CONCLUSIONS: Younger age and shorter duration of symptoms were associated with DKA in new-onset T1D. Despite availability of international guidelines, there was inconsistency in acute DKA management. These call for a need to raise public awareness on childhood diabetes as well as standardization of practice in management of pediatric DKA in Hong Kong.

Sensitivity Training for Mothers With Premature Infants: A Randomized Controlled Trial.

OBJECTIVE: This single-blind parallel design randomized controlled trial evaluated the feasibility and effectiveness of a modified version of the Mother-Infant Transaction Program (MITP) in enhancing Chinese mothers' sensitivity towards their premature infants' physiological and social cues. METHODS: Sixty mothers of hospitalized premature infants (mean gestational age = 32.1 weeks; SD = 2.8) were randomly assigned to either the MITP group or the treatment-as-usual control group. The intervention group (n = 30) received four sessions of parental sensitivity training adapted from the MITP, delivered by clinical psychologists before the infants were discharged. The control group (n = 30) received standard care provided by the hospitals. Each dyad was assessed at baseline (Time 1), immediately after intervention (Time 2), and when the infants were at the gestation-corrected ages of 3, 6, 9, and 12 months (Times 3-6). Maternal sensitivity, mother-infant interaction quality, parenting stress, postpartum depression, and mother's perception of infant's temperament were measured at Times 1-4, whereas infants' weight gain and developmental performance were assessed at Times 3-6. RESULTS: The MITP group showed significantly higher maternal sensitivity and better mother-infant interaction quality after completing the training. They also reported less parenting stress and postnatal depression than the control group at Time 2 and subsequent follow-ups. The intervention significantly predicted better weight gain and developmental outcomes in infants across Times 3-6, mediated by maternal wellbeing and interaction quality. CONCLUSION: Our results demonstrated the feasibility and effectiveness of this adapted sensitivity training among Chinese mothers with premature infants. [ClinicalTrials.gov NCT04383340].

Incidence and clinical characteristics of pediatric-onset type 2 diabetes in Hong Kong: The Hong Kong childhood diabetes registry 2008 to 2017.

OBJECTIVE: With increasing prevalence of childhood obesity worldwide, the incidence of pediatric-onset type 2 diabetes (T2D) is also increasing in many countries. We aim to analyze the time trend and incidence of T2D in children in Hong Kong from 2008 to 2017, and to characterize clinical characteristics at diagnosis. METHODS: Data were retrieved from the Hong Kong Childhood Diabetes Registry. All children with T2D diagnosed at the age of less than 18 years from January 1, 2008 to December 31, 2017 and managed in the public health care system were included in this study. RESULTS: In the incident years of 2008-2017 period, 391 children were diagnosed with T2D. The crude incidence rate was 3.42 per 100,000 persons/year [95% confidence interval (CI) 3.08-3.76], which was much higher than that in last registry of 1.27 per 100,000 persons/year in 1997-2007 (P < 0.001).Most children (76%) were asymptomatic and were diagnosed by routine screening. At presentation, a significant proportion presented with co-morbidities including fatty liver (37.9%), dyslipidaemia (35.3%), hypertension (22.5%), and microalbuminuria (12.8%). CONCLUSIONS: The incidence of T2D in children has increased significantly in Hong Kong. Most of them were asymptomatic and picked up on routine health screening. Yet, comorbidities were commonly identified at diagnosis.

False-positive SARS-CoV-2 serology in 3 children with Kawasaki disease.

BACKGROUND: Kawasaki disease (KD) is an acute febrile and eruptive disease with systemic vasculitis predominantly affecting young East Asian children. Recent reports showed that children with KD-like disease from KD low prevalence regions had positive SARS-CoV-2 serology despite a negative SARS-CoV-2 polymerase chain reaction (PCR) in respiratory samples. OBJECTIVES: To describe 3 pediatric Kawasaki Disease patients with false positive SARS-CoV-2 serology. STUDY DESIGN: We retrospectively recruited children with KD diagnosed during the COVID-19 outbreak in Hong Kong. Clinical characteristics and laboratory test results including SARS-CoV-2 PCR results were retrieved. We performed a microparticle-based immunoassay for the detection of IgG against nucleoprotein (NP) and spike protein receptor binding domain (RBD), and a microneutralization assay for the detection of neutralizing antibodies. RESULTS: Three Chinese children with typical KD were identified. They had no epidemiological links with COVID-19 patients and tested negative for SARS-CoV-2 NPA PCR. They were treated with IVIG and aspirin, and were discharged without complications. Subsequently 2 of them were tested positive against anti-RBD and anti-NP antibodies and 1 was tested positive against anti- RBD antibodies. However, microneutralization assay showed that neutralizing antibodies were absent, suggesting a false-positive IgG result. CONCLUSION: Detection of neutralizing antibodies is recommended to confirm previous SARS-CoV-2 infection in IgG-positive but PCR-negative patients.

Increasing incidence of type 1 diabetes among Hong Kong children and adolescents: The Hong Kong Childhood Diabetes Registry 2008 to 2017.

OBJECTIVE: The incidence of childhood-onset type 1 diabetes (T1D) has been reported to be rising but there is also evidence that it has been attenuated in recent years. We described the time trends and the incidence of T1D in children in Hong Kong from 2008 to 2017 and compared with the previous local registry in 1997 to 2007. METHODS: Data were extracted from the Hong Kong Childhood Diabetes Registry, which was established in 2016. It consists of a retrospective registry (including all childhood diabetes diagnosed in 2008 to 2015) and a prospective registry (including all T1D children diagnosed from 2016 onwards). All T1D children diagnosed at the age of less than 18 years from 1 January 2008 to 31 December 2017 and managed in the public system were included in this study. RESULTS: For the incident years in the 2008 to 2017 period, a total of 498 children with T1D was identified. The crude incidence rate was 4.3 per 100 000 person/year (95% confidence interval 3.96-4.72), which was much higher than the last registry of 2.2 per 100 000 persons/year. Using general linear model, the increment is statistically significant (P = .02). When compared to the last registry, the rate of increment had attenuated, with annual increment in crude incidence in the two periods for T1D <15 years changing from 4.3% to 3.5% (P = .02). CONCLUSIONS: The incidence of T1D children increased significantly in the past two decades in Hong Kong, but the rate of increase had attenuated in recent years.

Diagnosis of 5α-reductase 2 deficiency: is measurement of dihydrotestosterone essential?

BACKGROUND: 5α-Reductase 2 deficiency (5ARD) is a known cause of 46,XY disorders of sex development (DSD). Traditionally, the diagnosis relies on dihydrotestosterone (DHT) measurement, but the results are often equivocal, potentially leading to misdiagnosis. We reviewed alternative approaches for diagnosis of 5ARD. METHODS: We conducted a retrospective review of the results of urinary steroid profiling (USP) by GC-MS and mutational analysis of SRD5A2 [steroid-5-alpha-reductase, alpha polypeptide 2 (3-oxo-5 alpha-steroid delta 4-dehydrogenase alpha 2)] by PCR and direct DNA sequencing of all 46,XY DSD patients referred to our laboratory with biochemical and/or genetic findings compatible with 5ARD. We also performed a literature review on the laboratory findings of all 5ARD cases reported in the past 10 years. RESULTS: Of 16 patients diagnosed with 5ARD between January 2003 and July 2012, 15 underwent USP, and all showed characteristically low 5α- to 5ß-reduced steroid metabolite ratios. Four patients had DHT measured, but 2 did not reach the diagnostic cutoff. In all 12 patients who underwent genetic analysis, 2 mutations of the SRD5A2 gene were detected to confirm the diagnosis. Twenty-four publications involving 149 patients with 5ARD were published in the review period. Fewer than half of these patients had DHT tested. Nearly 95% of them had the diagnosis confirmed genetically. CONCLUSIONS: 5ARD can be confidently diagnosed by USP at 3 months postnatally and confirmed by mutational analysis of SRD5A2. Interpretation of DHT results may be problematic and is not essential in the diagnosis of 5ARD. We propose new diagnostic algorithms for 46,XY DSD.

Risk factors for post-operative complications in Chinese children with tonsillectomy and adenoidectomy for obstructive sleep apnea syndrome.

PURPOSE: Tonsillectomy and adenoidectomy (T&A) is commonly performed in children with obstructive apnea syndrome (OSAS). It was our hospital practice to observe all patients post T&A in the pediatric intensive care unit. We aim to describe the post-operative complications after tonsillectomy and adenoidectomy in children with OSAS and to identify risk factors for these complications. METHOD: Medical records of patients from 1 to 16 years old with OSAS and T&A done in this department were retrieved for analysis from April 1999 to July 2006. Information of the individual patients including the demographic data, polysomnography data, and presence of post-operative complications were recorded and analyzed. RESULTS: A total of 86 patient records were analyzed (M/F = 69:17). The mean BMI z score was 1.13 ± 1.53, and 36% of patients were classified as obese with z > 1.96. The median apnea-hypopnea index (AHI) before T&A was 9.8 episodes/h. Only six patients had post-operative desaturation. No bleeding complications were reported in our cohort. It was found that patients with desaturation after T&A had significantly higher mean BMI z score than children without desaturation (p = 0.014). There was otherwise no significant difference between the age, sex, AHI score, and the history of allergic rhinitis or asthma between the two groups. CONCLUSION: Our results showed that most children with OSAS underwent T&A without complications. The respiratory complication rate was 7%, and desaturation was the most common post-operative complication. Children with higher BMI z score were more likely to have desaturation after T&A (p = 0.014). Hence, careful monitoring with pulse oximeter after T&A should be offered to those who are obese.

The correlation among obesity, apnea-hypopnea index, and tonsil size in children.

BACKGROUND: The correlation between obesity and severity of obstructive sleep apnea (OSA) is well established in adults, but data are inconsistent in children. We hypothesized that there is a significant correlation between the degree of obesity and the severity of OSA in children. METHODS: We retrospectively reviewed records of weight, height, history, and polysomnography of all 1- to 15- year-old children referred to our sleep laboratory. Children with known anomalies and repeated polysomnography were excluded from this study. Obesity was defined as body mass index z score (BMI Z score) > 1.96. The correlation between BMI Z score and apnea-hypopnea index (AHI) was assessed. Possible confounding factors, ie, age, gender, and tonsil size, were adjusted by multiple linear regression. RESULTS: Four hundred eighty-two children were included in this study. Obese children had a significantly higher AHI (median, 1.5; interquartile range [IQR], 0.2 to 7.0) than the AHI of nonobese children (median, 0.7; IQR, 0.0 to 2.5). BMI Z score was significantly correlated with log-transformed AHI (Ln[AHI]) [r = 0.156, p = 0.003]. BMI Z score and tonsil size were still correlated with Ln(AHI) even after adjusted for other confounding factors (p = 0.001). CONCLUSION: Degree of obesity as measured by BMI Z score and tonsil size are significantly related to severity of OSA as reflected by the AHI, although the correlation is mild.

DNA-based subtyping of glycogen storage disease type III: mutation and haplotype analysis of the AGL gene in Chinese.

Glycogen storage disease type III (GSD III) is an inborn error of glycogen metabolism caused by a deficiency of glycogen debranching enzyme (AGL). Here, we investigate two unrelated Hong Kong Chinese GSD III patients and identify a novel 5-base pair deletional mutation, 2715_2719delTCAGAin exon 22, in one patient and a nonsense mutation, 1222C>T (R408X) in exon 11, in another patient. Since GSD IIIb is only caused by mutation in exon 3 of the AGL gene, we diagnose our patients to have GSD IIIa, which is consistent with the clinical diagnosis. Until now, R408X has only been reported in Faroe Islands GSDIII patients and was thought to demonstrate a founder effect. In this study, haplotyping of the disease-bearing chromosomes in the AGL locus by 19 intragenic single nucleotide polymorphisms shows that R408X is linked with IVS16+8T and IVS23-21T in our patient while R408X is linked with IVS16+8C and IVS23-21A in the Faroe Islands. The different haplotypes of R408X in Chinese and Faroese indicated that R408X is a recurrent mutation.

A case of fatal pharyngitis.

Pharyngitis is a common condition and usually does not lead to any major complication. We report a case in which the patient presented with pharyngitis resulting in an unusual fatal complication of pharyngeal and cerebral abscess. The causative organism was Streptococcus milleri that should be readily treatable by penicillin if the condition was recognised earlier.